Method for treating medical devices using glycerol and an antimicrobial agent

ABSTRACT

A non-metallic medical device treated with a antimicrobial agents is provided. Different combinations of antimicrobial agents can be used for different types of non-metallic medical devices depending on the types of infections related to each device. The combination of different antimicrobial substances has a synergistic effect against certain bacteria and fungi. An antimicrobial agent can be used to treat a non-metallic medical device by mixing the antimicrobial agent with an acid solution and glycerol and exposing the non-metallic medical device to the resulting mixture such that an enough of the antimicrobial agent binds to a portion of the non-metallic medical device to inhibit the growth of bacterial and fungal organisms.

FIELD OF INVENTIONS

[0001] The present invention relates to indwelling or implanted medicaldevices treated with an antimicrobial agent to inhibit the growth ofbacterial and fungal organisms. The invention also relates to a methodof treating indwelling or implanted medical devices with anantimicrobial agent.

BACKGROUND

[0002] Indwelling medical devices such as catheters are becomingessential to patient care. The benefit derived from these catheters,orthopedic devices, and other types of medical implants, however, isoften offset by infectious complications.

[0003] Some of the common organisms causing infectious complicationsassociated with indwelling medical devices are Staphylococcusepidermidis and Staphylococcus aureus. In the case of vascularcatheters, these two organisms account for almost 70-80% of allinfectious organisms, with Staphylococcus epidermidis being the mostcommon organism. Gram-negative bacilli cause about 15-20% of theinfections, and Candida species, a fungal agent, accounts for about10-15% of the vascular catheter infections. Other gram-negative bacteriaand fungal organisms (Candida) account for the remaining one-third ofcases.

[0004] Another common hospital-acquired infection is a urinary tractinfection (UTI). The majority of UTI cases are associated with the useof urinary catheters, including transurethral foley, suprapubic andnephrostomy catheters. These urinary catheters are inserted in a varietyof populations, including the elderly, stroke victims, spinalcord-injured patients, postoperative patients and those with obstructiveuropathy. Despite adherence to sterile guidelines for the insertion andmaintenance of urinary catheters, catheter-associated UTI continues topose a major problem. In the U.S. alone, about 1 million cases ofhospital-acquired cases of UTI occur annually. For instance, it isestimated that almost one-quarter of hospitalized spinal cord-injuredpatients develop symptomatic UTI during their hospital course.Gram-negative bacilli account for almost 60-70%, enterococci for about25% and Canada species for about 10% of cases of UTI.

[0005] Colonization of bacteria on the surfaces of the implant or otherparts of the device can produce serious patient problems, including theneed to remove and/or replace the implanted device and to vigorouslytreat secondary infective conditions. A considerable amount of attentionand study has been directed toward preventing such colonization by theuse of antimicrobial agents, such as antibiotics, bound to the surfaceof the materials employed in such devices. In such attempts, theobjective has been to produce a sufficient bacteriostatic orbactericidal action to prevent colonization.

[0006] Various methods have previously been employed to preventinfection of medical devices. A simple method is to flush the surfacesof a device with an antimicrobial solution. Generally, this flushingtechnique requires convenient access to the implantable device. Forexample, catheters are generally amenable to flushing with a solution ofrifampin and minocycline or rifampin and novobiocin. For use in flushingsolutions, the effective concentration of the antibiotic range fromabout 1 to 10 mg/ml for minocycline, preferably about 2 mg/ml; 1 to 10mg/ml for rifampin, preferably about 2 mg/ml; and 1 to 10 mg/ml fornovobiocin, preferably about 2 mg/ml. The flushing solution is normallycomposed of sterile water or sterile saline solutions.

[0007] Other methods of coating surfaces of medical devices withantimicrobial agents are taught in U.S. Pat. No. 4,895,566 (a medicaldevice substrate carrying a negatively charged group having a pKa ofless than 6 and a cationic antibiotic bound to the negatively chargedgroup); U.S. Pat. No. 4,917,686 (antibiotics are dissolved in a swellingagent which is absorbed into the matrix of the surface material of themedical device); U.S. Pat. No. 4,107,121 (constructing the medicaldevice with ionogenic hydrogels, which thereafter absorb or ironicallybind antibiotics); U.S. Pat. No. 5,013,306 (laminating an antibiotic toa polymeric surface layer of a medical device); U.S. Pat. No. 4,952,419(applying a film of silicone oil to the surface of an implant and thencontacting the silicone film bearing surface with antibiotic powders);and U.S. Pat. No. 4,442,133.

[0008] These and other methods of coating medical devices withantimicrobial agents appear in numerous patents and medical journalarticles. However, these methods also have significant drawbacks in thatthey can alter the integrity of non-metallic medical devices or resultin residual antimicrobial material precipitating within the device.

[0009] Accordingly, there is a need for a non-metallic medical devicetreated with an antimicrobial agent to provide a broad range ofantimicrobial activity while minimizing the harmful side effects notedabove. Further, there is a need for a method that results in lowresidual coating material left on the surface of the medical device,which reduces complications arising from precipitation of coatingmaterial within the device. There is also a need to enhance theversatility of the treatment to accommodate higher concentrations ofantimicrobial agents if needed.

SUMMARY OF THE INVENTION

[0010] One aspect of the present invention is a method for treatingnon-metallic medical devices with an antimicrobial agent comprising thesteps of mixing at least an antimicrobial agent, an acid solution, andglycerol to form an antimicrobial composition and applying theantimicrobial composition to at least a portion of the non-metallicmedical device under conditions wherein an effective concentration ofthe antimicrobial composition binds to the non-metallic medical device.

[0011] In a specific embodiment, the antimicrobial composition may beformed by mixing antimicrobial agents and an acid solution and thenadding glycerol.

[0012] In another specific embodiment, the antimicrobial agent may beselected from the chlorhexidine and methylisothiazolone; chlorhexidineand α-terpincol; thymol and chloroxylenol; thymol andmethylisothiazolone; chlorhexidine and cetylpyridinium chloride;chlorhexidine and chloroxylenol; chlorhexidine, methylisothiazolone andthymol; methylisothiazolone and α-terpineol; minocycline and rifampin;and chlorhexidine, methylisothiazolone and α-terpineol.

[0013] In another specific embodiment, the portion of the non-metallicmedical device treated may be made from rubber, plastic, nylon,silicone, polyurethane, polyethylene, polyvinyl chloride,polytetrafluoroethylene tetraphthalate, polyethylene tetraphthalate,polytetrafluoroethylene, latex, elastomers, polymers, and materialssealed with gelatin, collagen or alumin.

[0014] In another specific embodiment, the non-metallic medical devicemay be a peripherally insertable central venous catheter, dialysiscatheter, long term tunneled central venous catheter, peripheral venouscatheter, short-term central venous catheter, arterial catheter,pulmonary artery Swan-Ganz catheter, urinary catheter, long termnon-tunneled central venous catheters, peritoneal catheters, ventricularcatheters, long term urinary devices, tissue bonding urinary devices,penile prostheses, vascular grafts, extravascular grafts, urinarystints, vascular catheter ports, wound drain tubes, hydrocephalusshunts, pacemaker systems, artificial urinary sphincters, vasculardialators, extravascular dialators, vascular stints, extravascularstints, small joint replacements, temporary joint replacements, urinarydilators, heart valves, orthopedic implants, heart assist devices,stents, penial implants, mammary implants, and dental devices.

[0015] In another specific embodiment, the acid solution may be a shortchain monocarboxylic acid and ortho-phosphoric acid. The short chainmonocarboxylic acid may be formic acid, acetic acid, or propionic acid.

[0016] A further specific embodiment includes the ratio ofmonocarboxylic acid to ortho-phosphoric acid to glycerol may be about79:8:13.

[0017] In another specific embodiment, the antimicrobial composition hasa temperature that is between 2° C. to 75° C. at some point during thetreatment, preferably about 45° C.

[0018] In another specific embodiment, the acid solution may alsocontain potassium chloride.

[0019] In another specific embodiment, the antimicrobial composition maybe applied by exposing the non-metallic medical device to theantimicrobial composition for about 10 minutes to about 18 hours,preferably about 60 minutes.

[0020] In another specific embodiment, the method of treating thenon-metallic medical device may further comprise the step of removingexcess antimicrobial composition from the non-metallic medical deviceafter the application step and then drying the non-metallic medicaldevice. The non-metallic medical device may be dried for about 16 hours.

[0021] In another specific embodiment, the non-metallic medical devicemay be flushed with water after the drying step and may then be driedagain for about 10 hours to about 24 hours.

[0022] A further embodiment of the invention provides for an implantablemedical device comprising a body; one or more non-metallic surfaces onsaid body, glycerol, and an antimicrobial agent, wherein the glyceroland an effective concentration of the antimicrobial agent coat the oneor more non-metallic surfaces.

[0023] In another specific embodiment, the antimicrobial agent may beselected from the group consisting of chlorhexidine andmethylisothiazolone; chlorhexidine and α-terpineol; thymol andchloroxylenol; thymol and methylisothiazolone; chlorhexidine andcetylpyridinium chloride; chlorhexidine and chloroxylenol;chlorhexidine, methylisothiazolone and thymol; methylisothiazolone andα-terpineol; minocycline and rifampin; and chlorhexidine,methylisothiazolone and α-terpineol.

[0024] In another specific embodiment, the device may consist, at leastin part, of rubber, plastic, silicone, polyurethane, polyethylene,polytetrafluoroethylene and polyethylene tetraphthalate and polyethylenetetraphthalate sealed with gelatin, collagen or albumin.

[0025] In another specific embodiment, the non-metallic medical devicemay be a peripherally insertable central venous catheter, dialysiscatheter, long term tunneled central venous catheter, peripheral venouscatheter, short-term central venous catheter, arterial catheter,pulmonary artery Swan-Ganz catheter, urinary catheter, long termnon-tunneled central venous catheters, peritoneal catheters, ventricularcatheters, long term urinary devices, tissue bonding urinary devices,penile prostheses, vascular grafts, extravascular grafts, urinarystints, vascular catheter ports, wound drain tubes, hydrocephalusshunts, pacemaker systems, artificial urinary sphincters, vasculardialators, extravascular dialators, vascular stints, extravascularstints, small joint replacements, temporary joint replacements, urinarydilators, heart valves, orthopedic implants, heart assist devices,stents, penial implants, mammary implants, and dental devices.

DETAILED DESCRIPTION

[0026] It is readily apparent to one skilled in the art that variousembodiments and modifications may be made to the invention disclosed inthis application without departing from the scope and spirit of theinvention.

[0027] As used in the specification, “a” or “an” means one or more. Asused in the claims (s), when used in conjunction with the word“comprising,” the words “a” or “an” mean more or more. As used herein,“another” means at least a second or more.

[0028] The term “antimicrobial agent” as used in the present inventionmeans any single or combination of antiseptics, antibiotics,disinfectants, and antimicrobial peptides. Some examples antimicrobialagents include, but are not limited to, methylisothiazolone, thymol,α-terpineol, cetylpyridinium chloride, chloroxylenol, hexachlorophene,chlorhexidine and other cationic biguanides, methylene chloride, iodineand iodophores, triclosan, taurinamides, nitrofurantoin, methenamine,aldehydes, azylic acid, silver, benzyl peroxide, alcohols, carboxylicacids, salts, erythromycin, nafcillin, cefazolin, imipenem, astreonam,gentamicin, sulfamethoxazole, vancomycin, ciprofloxacin, trimethoprim,rifampin, metronidazole, clindamycin, teicoplanin, mupirocin,azithromycin, clarithromycin, ofoxacin, lomefloxacin, norfloxacin,nalidixic acid, sparfloxacin, pefloxacin, amifloxacin, gatifloxacin,moxifloxacin, gemifloxacin, enoxacin, fleroxacin, minocycline,linexolid, temafloxacin, tosufloxacin, clinafloxacin, sulbactam,clavulanic acid, amphotericin B, fluconazole, itraconazole,ketoconazole, nystatin, penicillins, cephalosporins, carbepenems,beta-lactams antibiotics, aminoglycosides, macrolides, lincosamides,glycopeeptides, tetracylines, chloramphenicol, quinolones, fucidines,sulfonamides, trimethoprims, rifamycins, oxalines, streptogramins,lipepeptides, ketolides, polyenes, azoles, and echinocandines. Otherexamples of antibiotics, such as those listed in Sakamoto et al, U.S.Pat. No. 4,642,104 herein incorporated by reference will readily suggestthemselves to those of ordinary skill in the art.

[0029] These antimicrobial agents are preferably used in combinations oftwo or more to obtain a synergistic effect. They are dispersed along thesurface of the medical device to provide a broad range of antimicrobialactivity.

[0030] Some examples include chlorhexidine and methylisothiazolone;chlorhexidine and α-terpineol; thymol and chloroxylenol; thymol andmethylisothiazolone; chlorhexidine and cetylpyridinium chloride;chlorhexidine and chloroxylenol; chlorhexidine, methylisothiazolone andthymol; methylisothiazolone and α-terpineol; minocycline and rifampin;and chlorhexidine, methylisothiazolone and α-terpineol. Thesecombinations provide a broad spectrum of activity against a wide varietyof organisms.

[0031] The amount of antimicrobial agent used to treat a medical devicevaries to some extent, but is at least a sufficient amount to form aneffective concentration to inhibit the growth of bacterial and fungalorganisms, such as staphylococci, gram-positive bacteria, gram-negativebacilli and Candida.

[0032] The term “effective concentration” means a sufficient amount ofan antimicrobial agent to decrease, prevent or inhibit the growth ofbacterial and/or fungal organisms. The amount will vary for eachcompound and upon known factors such as pharmaceutical characteristics;the type of medical device; age, sex, health and weight of therecipient, and the use and length of use. It is within the skilledartisan's ability to relatively easily determine an effectiveconcentration of an antimicrobial agent for different antimicrobialagents and different known factors.

[0033] The antimicrobial agents may antiseptics. The use of antisepticsmay provide more efficacy against gram-negative bacteria and Candidaspecies than antibiotic combinations. Although the different mixtures ofantiseptics can be used for all medical devices, certain mixtures workbetter with different devices. Different combinations of antiseptics canbe used for different types of medical devices depending on the spectrumof organisms that cause the infections related to each device. Forinstance, preferred combinations of treating orthopedic devices includechlorhexidine, methylisothiazolone and α-terpineol; chlorhexidine andcetylpyridinium chloride; chlorhexidine and chloroxylenol; orchlorhexidine, methylisothiazolone and thymol. The combination ofdifferent antiseptics has a synergistic effect against certain bacteriaand fungi.

[0034] The term “bacterial and fungal organisms” as used in the presentinvention means all genera and species of bacteria and fungi, includingbut not limited to all spherical, rod-shaped and spiral organisms. Oneskilled in the art recognizes that a variety of source books which listand describe bacteria and fungi are available, for example in thetextbook “Principles and Practice of Infectious Diseases”, Mandell etal., 4^(th) edition, 1995, Churchill Livingstone, N.Y. Some examples ofbacteria are staphylococci (i.e. Staphylococcus epidermidis,Staphylococcus aureus), Enterococcus faecalis, Pseudomonas aeruginosa,Escherichia coli, other gram-positive bacteria and gram-negativebacilli. One example of a fungus is Candida albicans.

[0035] The term “glycerol” means glycerol or glyceride.

[0036] As used herein “implanted” devices includes both temporary andpermanent devices and indwelling and implanted devices.

[0037] The medical devices which are amenable to treatment according toone aspect of the present invention are non-metallic. However,non-metallic portions or components of metallic devices may be treated.Treatable medical devices may also include devices that are formed frommore than one type of non-metallic material.

[0038] Non-metallic materials that can be treated by the method of thepresent invention include, but are not limited to, rubber, plastic,nylon, silicone, polyurethane, polyethylene, polyvinyl chloride, Gortex(polytetrafluoroethylene tetraphthalate), Dacron (polyethylenetetraphthalate), Teflon (polytetrafluoroethylene), latex, elastomers,polymers, and materials sealed with gelatin, collagen or albumin.

[0039] Particular non-metallic medical devices suited for theantimicrobial treatment of the present invention include, but are notlimited to, peripherally insertable central venous catheters, dialysiscatheters, long term tunneled central venous catheters, long termnon-tunneled central venous catheters, peripheral venous catheters,short-term central venous catheters, arterial catheters, pulmonary artySwan-Ganz catheters, urinary catheters, long term urinary devices,tissue bonding urinary devices, penile prostheses, vascular grafts,extravascular grafts, urinary stints, vascular catheter ports, wounddrain tubes, hydrocephalus shunts, peritoneal catheters, pacemakersystems, artificial urinary sphincters, vascular dialators,extravascular dialators, vascular stints, extravascular stints,ventricular catheters, small joint replacements, temporary jointreplacements, urinary dilators, heart valves, orthopedic implants, heartassist devices, stents, penial implants, mammary implants, dentaldevices, and the like.

[0040] In addition to treating non-metallic medical devices, the presentinvention may also be used to treat miscellaneous surfaces, such ashospital floors, nursing counters, counters adjacent to washing basins,desks, etc. to decrease transmission of hospital antibiotic-resistantmicrobial flora, such as methicillin-resistant staphylococcus aureus,vancomycin-resistant enterococci and antibiotic-resistant gram negativebacteria on the skin of health care personnel and patients. Anotherpotential application is the treatment of kitchen counters to decreasetransmission of organisms that cause food-borne poisoning, such asSalmonella species and Escherichia coli.

[0041] The non-metallic medical device may be treated with anantimicrobial composition by applying a sufficient amount of theantimicrobial composition to at least a portion of the medical deviceunder conditions wherein at least a portion of the antimicrobialcomposition binds with the non-metallic portions of the medical device.Although it is contemplated that the antimicrobial agents will bind withthe medical device, other ingredients such as anti coagulants andanti-inflammatory agents may be included in the antimicrobialcomposition and may also bind with the medical device. It is alsocontemplated that a non-metallic medical device may be treated with acomposition of non-antimicrobial agents.

[0042] The following examples are offered by way of illustration and arenot intended to limit the invention in any manner.

EXAMPLE 1 Method for Treating Non-Metallic Medical Devices

[0043] The treatment solution consists of a solvent of a saturated shortchain monocarboxylic acid such as formic acid, acetic acid, andpropionic acid with a liquidity state below 90° C. and above 10° C. anda pKa of 3 to 5. The formic acid solution is 88% formic acid. It ismixed with an 85% ortho-phosphoric acid solution (for uniformity ofcoating), 10 mg of potassium chloride per ml of the mixture of formicacid and ortho-phosphoric acid to get a homogeneous solution (potassiumions facilitate surface binding by increasing the ionic strength), andglycerol. The glycerol or glycerin is used as a plasticizer and avehicle solvent. It also acts as a lubricant between polymer chains toprevent the polymer from becoming brittle during the treatment process.The glycerol also forms hydrogen bonding with its hydroxyl groups [—OH]with the polymer as well as the antimicrobial agents during thetreatment process facilitating the incorporation of coating agents(antimicrobial or non-antimicrobial) into the medical device. The totalvolume of the resulting coating mixture can be composed of 79% formicacid solution (range between 10% to 90%), 8% ortho-phosphoric acidsolution (range between 5% to 10%), and 13% glycerin (range between 8%to 15%). The antimicrobial agents (such as minocycline and rifampin) areadded to the solution before addition of glycerin to avoid dissolutionat a higher viscosity that glycerin adds to the coating solution. Forinstance, minocycline and rifampin are added at concentrations of up to300 mg per ml of the total volume of the coating solution. The additionorder of these antibiotics is not important; however, monitoring thedissolution of minocycline is easier before adding rifampin. Beforeimmersing the non-metallic medical devices in the final treatingsolution, the solution's temperature should be elevated from the roomtemperature to around 45° C. (range between 2° C. to 75° C.) but wellbelow the lowest boiling point of any component. At lower temperaturesthe treatment time may be increased up to 18 hours. After reaching thedesired temperature, the device is completely submerged into thesolution for a period of time that can vary depending on the nature ofthe polymer to be coated. This period can be 1 hour with a range betweenabout 10 minutes to about 18 hours. However, for more rigid polymerssuch as polyethylene or polytetrafluoroethylene this period also couldbe elongated accordingly as long as the integrity of the polymer remainsintact. The coating and drying steps should be preformed primarily inthe dark to avoid unwanted free radical reactions.

[0044] After the treatment period, the device is removed and shakenvigorously or purged with nitrogen gas to remove any excess solutionfrom the device. The device is then placed under a well-ventilated fumehood for at least 16 hours (it is recommended to dry for 48 hours toinsure removal of excess glycerin and formic acid). This drying step isoptimally performed in the dark. After the drying period the device isrinsed and flushed with deionized water and placed back under the fumehood for another 10-24 hour period.

EXAMPLE 2 Synergy of an Antiseptic Combination Used to TreatNon-Metallic Medical Devices

[0045] Catheter segments were coated with a solution containing 30 ml of88% formic acid, 3 ml of 85% ortho-phosphoric acid, 400 mg of potassiumchloride, 2000 mg of rifampin (50 mg/ml), 1000 mg of minocycline (25mg/ml), and 5 ml of glycerol at a total of about 40 ml final solutionaccording to the described method for one hour at 45° C. After therinsing and drying process the antimicrobial activity of the coatedcatheters were measured by performing a modified Kirby-Bauer method.Three one-centimeter segments were set aside for each organism forbaseline antimicrobial activity. Another twelve segments were placed inserum at 37° C. for each organism tested. Samples were removed after 3days, 7 days, 10 days, and 14 days. After removal of samples from serum,the remaining segments were placed in new serum. Zones of inhibitionwere performed for baseline, day 3, day 7, day 10, and day 14 againstStaphylococcus epidermidis, Escherichia coli, and Candida albicansaccording to Kirby-Bauer method. Each segment was half embedded in thecenter of a Muller-Hinton agar plate that had been previously inoculatedwith individual organisms. Prior to placing the segments in agar, eachorganism was grown for 18 hours in trypticase soy broth to aconcentration of 0.5 McFarland U (10⁸ cfu/ml). A cotton swab was placedin the suspension and streaked across the surface of the Muller-Hintonagar plate to cover the entire plate. All plates were placed in a 37° C.incubator for 24 hours.

[0046] Zones of inhibition were measured the next day. The results areshown in Table 1. Additionally, medical devices with different outsidediameters were treated in the same way. The measured zones of inhibitionfor these medical devices are shown in Table 2. Tables 1 and 2demonstrate the broad-spectrum antimicrobial activity that can beachieved using the disclosed treatment method. TABLE 1 Mean Zones ofInhibition with Minocycline/Rifampin Coated Nylon Catheters (ExternalDiameter, 1 mm) Staphylococcus Epidermidis Escherichia coli Candidaalbicans Baseline (day 0) 40 10 8 Day 3 31 5 Not done Day 7 32 3 Notdone Day 10 22 3 3 Day 15 21 — —

[0047] TABLE 2 Mean Zones of Inhibition with other Minocycline/ RifampinCoated Catheters (mm) Staphylococcus Catheter (external diameter)epidermidis Escherichia coli Polyurethane introducer (4 mm) 37 13Polyurethane catheter (2 mm) 40 12 Silicone catheter (1 mm) 32 10

EXAMPLE 3 Non-Metallic Medical Devices Treated with an AntisepticComposition or an Antibiotic Composition Using Two Different AcidSolutions

[0048] Vascular catheters made out of four different materials weretested. The catheters were made out of nylon, polyurethane, silicone,and polyethylene. 6-cm catheter sections were treated using either Butylacetate/Methanol (85:15) (BA/ME) or Formic acid/Potassiumchloride/Phosphoric acid/Glycerin (30 ml:400 mg:3 ml:5 ml (FA/GL). Thechloroxylenol was dissolved in formic acid at 45° C. for 2 hours withlow agitation. The treatment solution used in the BA/ME method containedeither 25 mg/ml of minocycline and 40 mg/ml of rifampin, or 50 mg/ml ofchlorhexidine and 50 mg/ml of chloroxylenol. The treatment solution usedin the FA/GL method contained either 25 mg/ml of minocycline and 50mg/ml of rifampin, or 100 mg/ml of chlorhexidine and 100 mg/ml ofchloroxylenol.

[0049] The catheter sections were immersed in the treatment solution for60 minutes in the dark. The Catheter sections were then removed from thetreatment solutions and dried for 24 hours under a fume hood in thedark. Finally, the catheter sections were rinsed with deionizeddistilled water and placed back under the fume hood for another 24 hoursin the dark.

[0050] After the catheter sections were allowed to dry, 0.5-cm pieceswere cut from the end of each catheter section and disposed, and theremaining 5-cm coated catheter sections were cut into five 1-cmsegments. The 1-cm coated catheter segments were used to determine thezone of inhibition (measurement that represents the diameter of theclear zone perpendicular to the long axis of the 1-2 mm wide cathetersegment) against 3 types of organisms (Staphylococcus epidermidis,Escherichia coli, and Candida albicans), both at baseline (day 0) andafter incubation in serum at 37° C. (day 1, day 3, day 7, and day 14).The serum was replaced with new serum at days 1, 3, and 7. The zones ofinhibition were determined in triplicate for each of the specific groups(stratified according to type of coating method/type of antimicrobialcoating agents/type of catheter material/type of organism/time ofperforming zone of inhibition.)

[0051] The results are shown in Tables 3-6. The tables furtherdemonstrate the broad-spectrum antimicrobial activity achieved using thedisclosed treatment method. Tables 3-6 further demonstrate that thedisclosed method can be used to effectively treat various types ofnon-metallic materials. TABLE 3 BA/ME Coating Method UsingMinocycline/Rifampin (25M/40R) Average Zones of Inhibition in mm(Average of 3 Observations) Duration Organism Polyurethane NylonSilicone Polyethylene Baseline Staph. epi. 33 17 31 18  1 Day Staph.epi. 31 16 31 16  3 Days Staph. epi. 31 14 29 17  7 Days Staph. epi. 297 22 10 14 Days Staph. epi. 27 5 14 0 Baseline E. coli 8 2 8 0  1 Day E.coli 5 0 10 0  3 Days E. coli 4 0 0 0  7 Das E. coli 4 0 0 0 14 Days E.coli 5 0 0 0 Baseline Candida a. 12 0 13 0  1 Day Candida a. 9 0 6 0  3Days Candida a. 7 0 3 0  7 Days Candida a. 5 0 0 0 14 Days Candida a. 00 0 0

[0052] TABLE 4 BA/ME Coating Method Using Chlorhexidine/Chloroxylenol(50CH/50CX) Average Zones of Inhibition in mm (Average of 3Observations) Duration Organism Polyurethane Nylon Silicone PolyethyleneBaseline Staph. epi. 17 7 12 0  1 Day Staph. epi. 14 6 11 0  3 DaysStaph. epi. 12 6 10 0  7 Days Staph. epi. 12 5 8 0 14 Days Staph. epi. 85 3 0 Baseline E. coli 14 4 10 2  1 Day E. coli 9 2 7 0  3 Days E. coli8 0 6 0  7 Days E. coli 7 0 3 0 14 Days E. coli 5 0 0 0 Baseline Candidaa. 19 3 13 0  1 Day Candida a. 11 2 13 0  3 Days Candida a. 10 0 4 0  7Days Candida a. 9 0 0 0 14 Days Candida a. 2 0 0 0

[0053] TABLE 5 FA/GL Coating Method Using Minocycline/Rifampin (25M/50R)Average Zones of Inhibition in mm (Average of 3 Observations) DurationOrganism Polyurethane Nylon Silicone Polyethylene Baseline Staph. epi.35 28 23 23  1 Day Staph. epi. 32 24 16 9  3 Days Staph. epi. 27 17 18 6 7 Days Staph. epi. 23 15 10 3 14 Days Staph. epi. 23 11 4 2 Baseline E.coli 7 12 6 10  Day E. coli 4 4 6 4  3 Days E. coli 0 3 7 2  7 Das E.coli 0 3 6 0 14 Days E. coli 0 0 2 0 Baseline Candida a. 6 5 5 3  1 DayCandida a. 6 4 2 0  3 Days Candida a. 4 2 0 0  7 Days Candida a. 4 0 0 014 Days Candida a. 4 0 0 0

[0054] TABLE 6 FA/GL Coating Method Using Chlorhexidine/Chloroxylenol(100CH/100CX) Average Zones of Inhibition in mm (Average of 3Observations) Duration Organism Polyurethane Nylon Silicone PolyethyleneBaseline  Staph. epi. 33 33 20 18  1 Day  Staph. epi. 30 31 17 12  3Days  Staph. epi. 30 26 14 10  7 Days  Staph. epi. 28 23 12 21 14 Days Staph. epi. 26 27 14 10 Baseline  E. coil 19 21 21 15  1 Day  E. coli20 18 11 8  3 Days  E. coli 20 18 9 6  7 Days  E. coli 18 16 8 6 14 Days E. coli 21 17 7 7 Baseline  Candida a. 40 37 40 16  1 Day  Candida a.39 32 22 4  3 Days  Candida a. 32 28 19 6  7 Days  Candida a. 25 23 15 214 Days  Candida a. 32 25 7 3

[0055] All patents and publication mentioned in this specification areindicative of the levels of those skilled in the art to which theinvention pertains. All patents and publications are herein incorporatedby reference to the same extent as if each individual publication wasspecifically and individually indicated to be incorporated by reference.

[0056] The present invention, therefore, is well adapted to carry outthe objects and attain the ends and advantages mentioned as well asother inherent therein. While presently preferred embodiments of theinvention are given for the purpose of disclosure, numerous changes inthe details will readily suggest themselves to those skilled in the artand which are encompassed within the spirit of the invention; and thescope of the appended claims.

What I claim is:
 1. A method of treating a non-metallic medical devicewith an antimicrobial agent comprising the steps of: mixing at least anantimicrobial agent, an acid solution, and glycerol to form anantimicrobial composition; and applying the antimicrobial composition toat least a portion of the non-metallic medical device under conditionswherein an effective concentration of the antimicrobial compositionbinds to the non-metallic medical device.
 2. The method of claim 1,wherein the antimicrobial composition is formed by mixing theantimicrobial agents and the acid solution and then adding glycerol. 3.The method according to claim 1, wherein the antimicrobial agent isselected from the group of combinations consisting of chlorhexidine andmethylisothiazolone; chlorhexidine and α-terpineol; thymol andchloroxylenol; thymol and methylisothiazolone; chlorhexidine andcetylpyridinium chloride; chlorhexidine and chloroxylenol;chlorhexidine, methylisothiazolone and thymol; methylisothiazolone andα-terpineol; minocycline and rifampin; and chlorhexidine,methylisothiazolone and α-terpineol.
 4. The method according to claim 1,wherein the antimicrobial agent is comprised of a minocycline andrifampin.
 5. The method according to claim 1, wherein a portion of thenon-metallic medical device is made from material selected from thegroup consisting of rubber, plastic, nylon, silicone, polyurethane,polyethylene, polyvinyl chloride, polytetrafluoroethylenetetraphthalate, polyethylene tetraphthalate, polytetrafluoroethylene,latex, and materials sealed with gelatin, collagen or alumin.
 6. Themethod according to claim 1, wherein the non-metallic medical device isa catheter selected from the group consisting of peripherally insertablecentral venous catheter, dialysis catheter, long term tunneled centralvenous catheter, peripheral venous catheter, short-term central venouscatheter, arterial catheter, pulmonary artery Swan-Ganz catheter,urinary catheter, long term non-tunneled central venous catheters,peritoneal catheters, and ventricular catheters.
 7. The method accordingto claim 1, wherein the non-metallic medical device is selected from thegroup consisting of long term urinary devices, tissue bonding urinarydevices, penile prostheses, vascular grafts, extravascular grafts,urinary stints, vascular catheter ports, wound drain tubes,hydrocephalus shunts, pacemaker systems, artificial urinary sphincters,vascular dialators, extravascular dialators, vascular stints,extravascular stints, small joint replacements, temporary jointreplacements, urinary dilators, heart valves, orthopedic implants, heartassist devices, stents, penial implants, mammary implants, and dentaldevices.
 8. The method according to claim 1, wherein the acid solutionis comprised of short chain monocarboxylic acid and ortho-phosphoricacid.
 9. The method according to claim 8, wherein the volume ratio formonocarboxylic acid to ortho-phosphoric acid to glycerol is about79:8:13.
 10. The method according to claim 8, wherein the short chainmonocarboxylic acid is selected from the group consisting of formicacid, acetic acid, and propionic acid.
 11. The method according to claim1, wherein the antimicrobial composition has a temperature that reachesbetween 2° C. to 75° C. during the applying step.
 12. The methodaccording to claim 1, wherein the antimicrobial composition has atemperature that reaches about 45° C. during the applying step.
 13. Themethod according to claim 8, wherein the acid solution further comprisespotassium chloride.
 14. The method according to claim 1, wherein theantimicrobial composition is applied by exposing the non-metallicmedical device to the antimicrobial composition for about 10 minutes toabout 18 hours.
 15. The method according to claim 1, wherein theantimicrobial composition is applied by exposing the non-metallicmedical device to the antimicrobial composition for about 60 minutes.16. The method according to claim 1, further comprising the step of:removing excess antimicrobial composition from the non-metallic medicaldevice after applying the antimicrobial composition; and drying thenon-metallic medical device after removing the excess antimicrobialcomposition.
 17. The method according to claim 16, wherein the excessantimicrobial composition is removed with gaseous material.
 18. Themethod according to claim 17, wherein the gaseous material is nitrogen.19. The method according to claim 16, wherein the drying step lasts forabout 16 hours.
 20. The method according to claim 16, further comprisingthe step of flushing the non-metallic medical device with water afterthe drying step.
 21. The method according to claim 20, furthercomprising drying the non-metallic medical device after flushing thenon-metallic medical device with water.
 22. The method according toclaim 20, further comprising drying the non-metallic medical device fromabout 10 hours to about 24 hours after flushing the non-metallic medicaldevice with water.
 23. The method according to claim 1, wherein theantimicrobial agent is applied by dipping the non-metallic medicaldevice into the antimicrobial composition.
 24. An implantable medicaldevice comprising: a body; one or more non-metallic surfaces on saidbody, glycerol, and an antimicrobial agent, wherein the glycerol and aneffective concentration of the antimicrobial agent coat the one or morenon-metallic surfaces.
 25. The device of claim 24, wherein theantimicrobial agent is selected from the group consisting of:chlorhexidine and methylisothiazolone; chlorhexidine and α-terpineol;thymol and chloroxylenol; thymol and methylisothiazolone; chlorhexidineand cetylpyridinium chloride; chlorhexidine and chloroxylenol;chlorhexidine, methylisothiazolone and thymol; methylisothiazolone anda-terpineol; minocycline and rifampin; and chlorhexidine,methylisothiazolone and a-terpineol.
 26. The device of claim 24, whereinthe antimicrobial agent is comprised of a minocycline and rifampin. 27.The device of claim 24, where in the non-metallic material is selectedfrom the group consisting of rubber, plastic, nylon, silicone,polyurethane, polyethylene, polyvinyl chloride, polytetrafluoroethylenetetraphthalate, polyethylene tetraphthalate, polytetrafluoroethylene,latex, and materials sealed with gelatin, collagen or alumin.
 28. Thedevice of claim 24, wherein the non-metallic medical device is acatheter selected from the group consisting of peripherally insertablecentral venous catheter, dialysis catheter, long term tunneled centralvenous catheter, peripheral venous catheter, short-term central venouscatheter, arterial catheter, pulmonary artery Swan-Ganz catheter,urinary catheter, long term non-tunneled central venous catheters,peritoneal catheters, and ventricular catheters.
 29. The device of claim24, wherein the non-metallic medical device is selected from the groupconsisting of long term urinary devices, tissue bonding urinary devices,penile prostheses, vascular grafts, extravascular grafts, urinarystints, vascular catheter ports, wound drain tubes, hydrocephalusshunts, pacemaker systems, artificial urinary sphincters, vasculardialators, extravascular dialators, vascular stints, extravascularstints, small joint replacements, temporary joint replacements, urinarydilators, heart valves, orthopedic implants, heart assist devices,stents, penial implants, mammary implants, and dental devices.